MOLECULAR GENETICS OF AUTISM

自闭症的分子遗传学

• 批准号: 6336605
• 负责人: Edwin H Cook
• 金额: $ 26.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6336605
• 关键词: Asperger syndrome; autism; child behavior disorders; child mental disorders; family genetics; fragile X syndromes; genetic disorder diagnosis; genetic markers; genetic polymorphism; genotype; human genetic material tag; human subject; human tissue; linkage disequilibriums; molecular genetics; molecular pathology; neurobiology; polymerase chain reaction

Autism is a severe developmental disorder afflicting about 2-10 per 10,000 individuals. While twin and family studies support significant gene involvement, the specific mode of genetic inheritance is unknown and multiplicative gene action, genetic heterogeneity, and variable expression of underlying susceptibility genes are probable. Given the unknown and complex mode of genetic inheritance in autism, success in localizing underlying disease genes in autism will require evaluation of hundreds of genetic markers spanning the genome and large sample sizes to obtain sufficient power to find underlying genes. In addition, candidate gene studies based on function or position are complementary strategies in a comprehensive approach to understanding the molecular genetic basis of autism. The goals of this project are to localize disease genes in autism through a systematic genome search and candidate gene analysis. In a multi-site international collaborative effort, 240 families with affected sibling pairs with autism will be collected and genotyped on highly polymorphic markers spanning the human genome at regular, close intervals. The U.S. collaborative group will identify and phenotype 120 families with affected siblings with autism and send blood from the families to U.K. for transformation of cell lines. The U.K.-European group of collaborators, through their own funding resources, will collect an additional set of 120 relative pairs and genotyping efforts will be conducted in an independent laboratory facility. Through this international effort susceptibility genes can be identified in approximately 240 pairs. In addition candidate genes will be studied using the transmission/disequilibrium test for serotonergic. dopaminergic. GABAergic and associated disease candidates (tuberculous sclerosis). Linkage disequilibrium studies, conducted in 350 families with only one child with autism and 80 families with a child with Asperger's disorder will allow determination of whether there arc different susceptibility genes involved in simplex autism, multiplex autism, or Asperger's disorder. Once susceptibility genes for autism are identified, their role in the clinical variability in autism and in the expression of putative milder variants in autism, including social functioning deficits, mood, and anxiety disorders may be identified. In addition, identification of the genetic determinants in autism would lay the groundwork for development of improved treatment interventions targeting the pathophysiology of autism.

自闭症是一种严重的发育障碍，每 10,000 人中约有 2-10 人患有自闭症 个人。虽然双胞胎和家庭研究支持显着基因 参与，遗传的具体方式尚不清楚， 倍增基因作用、遗传异质性和可变表达 潜在的易感基因是可能的。鉴于未知和 自闭症遗传的复杂模式，成功定位 自闭症的潜在疾病基因需要评估数百个 跨越基因组的遗传标记和大样本量以获得 足够的力量来寻找潜在的基因。另外，候选基因 基于功能或职位的研究是互补策略 理解分子遗传基础的综合方法 自闭症。 该项目的目标是通过以下方式定位自闭症的疾病基因： 系统的基因组搜索和候选基因分析。在多站点中 国际合作努力，240 个有兄弟姐妹受影响的家庭 将收集患有自闭症的配对并进行高度多态性的基因分型 人类基因组中定期、紧密间隔的标记。美国 合作小组将识别 120 个受影响的家庭并对其进行表型分析 患有自闭症的兄弟姐妹，并将其家庭的血液送到英国进行治疗 细胞系的转化。英国-欧洲合作者小组， 通过自己的资金来源，将额外收集120套 相关配对和基因分型工作将在独立的机构中进行 实验室设施。通过这项国际努力，敏感性 可以鉴定大约 240 对基因。另外候选人 将使用传递/不平衡测试来研究基因 血清素能。多巴胺能。 GABA能及相关疾病候选者 （结核性硬化症）。连锁不平衡研究，在 350 人中进行 只有一名自闭症儿童的家庭和 80 个有一名自闭症儿童的家庭 阿斯伯格症将有助于确定是否存在 不同的易感基因涉及单发性自闭症、多发性自闭症 自闭症，或阿斯伯格症。一旦自闭症的易感基因被确定 确定了它们在自闭症临床变异和 自闭症中假定的较温和变异的表达，包括社交 可以识别功能缺陷、情绪和焦虑障碍。在 此外，确定自闭症的遗传决定因素将奠定 开发改进治疗干预措施的基础 针对自闭症的病理生理学。